Vitamin D for the management of multiple sclerosis

Vitamin D for the management of multiple sclerosis (Review)

Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010, Issue 12

http://www.thecochranelibrary.com

Vitamin D for the management of multiple sclerosis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

22INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iVitamin D for the management of multiple sclerosis (Review)


[Intervention Review]

Vitamin D for the management of multiple sclerosis

Vanitha A Jagannath1 , Zbys Fedorowicz2 , G V Asokan3 , Edward W Robak4 , Liz Whamond5

1Department of Paediatrics, KIMS Bahrain Medical Center, Manama, Bahrain. 2UKCC (Bahrain Branch), Ministry of Health, Bahrain,

Awali, Bahrain. 3College of Health Sciences, Ministry of Health, Manama, Bahrain. 4Faculty of Forestry and Environmental Manage-

ment, University of New Brunswick, Fredericton, Canada. 5Canadian Cancer Action Network, Fredericton, Canada

Contact address: Vanitha A Jagannath, Department of Paediatrics, KIMS Bahrain Medical Center, Um al Hassam Ave, Adliya, Manama,

PO Box 175829, Bahrain. [email protected]. [email protected].

Editorial group: Cochrane Multiple Sclerosis Group.

Publication status and date: New, published in Issue 12, 2010.

Review content assessed as up-to-date: 29 June 2010.

Citation: Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of multiple sclerosis.

Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008422. DOI: 10.1002/14651858.CD008422.pub2.


A B S T R A C T

Background

Multiple sclerosis is a disease of the central nervous system characterized by demyelination of the nerve sheaths which can result in

varying levels of disability. Disease occurrence and progression are considered by some to be associated with low serum levels of vitamin

D. Studies investigating vitamin D supplementation in MS patients have illustrated a noticeable improvement in the course of the

disease.

Objectives

To evaluate the safety and effectiveness of vitamin D in the management of multiple sclerosis.

Search strategy

We searched the Cochrane Multiple Sclerosis Group Trials Register comprising references identified from comprehensive electronic

database searches and hand searches of relevant journals and abstract books of conferences.

Selection criteria

Randomised and quasi-randomised controlled trials comparing vitamin D with placebo or any other treatment for the management of

multiple sclerosis.

Data collection and analysis

Two review authors selected trials for inclusion, assessed the risk of bias and extracted data independently. Disagreements were resolved

by consensus. Trialists were contacted for clarification of study details.

Main results

We included a single trial (49 participants) conducted over 52 weeks, which treated 25 patients with escalating doses of vitamin D

compared with control (24). The trial provided some evidence of the potential benefit of the intervention on several outcomes i.e. the

annualised relapse rate; EDSS scores; suppression of T-cell proliferation and illustrated a measure of comparative safety in the relative

absence of any adverse events or of high serum calcium levels over the study period. This was a low powered trial with a potential high

risk of bias which may ultimately impose limits on the applicability of the available evidence to the MS population as a whole.

1Vitamin D for the management of multiple sclerosis (Review)


mailto:[email protected]

mailto:[email protected]

Authors’ conclusions

The current level of evidence for the effectiveness of vitamin D supplementation in the management of people with MS is based on a

single RCT with potential high risk of bias, which does not at present allow confident decision-making about the use of Vitamin D

in MS. Therefore, until further high quality evidence is available, clinicians may wish to consider relevant MS guidelines on vitamin

D supplementation when making decisions about the care of people with multiple sclerosis. Adequately powered, multi-centred RCTs

with a focus on clinical as well as immunological and MRI outcomes that are meaningful to people with MS, and are able to provide

insight into the benefits of Vitamin D in people with MS, are still required.

P L A I N L A N G U A G E S U M M A R Y

Vitamin D for the management of multiple sclerosis

Multiple sclerosis is an illness in which the myelin sheaths around the nerves of the brain and spinal cord are damaged, affecting the

ability of nerve cells to communicate with each other. A wide range of clinical presentations and neurological symptoms can occur with

the disease, and these can progress to physical and cognitive disability often with a variable clinical course. Although very little is known

about the mechanism and causes of this disease genetic, immunologic and environmental factors have all been implicated. Studies have

shown a characteristic geographical pattern of disease distribution both in occurrence and progression, which appear to be correlated

with sun light exposure and lack of vitamin D and are considered to be predisposing factors for MS. Vitamin D deficiency is said to

affect the general well being of patients with MS and is also associated with poorer neurologic outcomes. People suffering with MS

are usually given regular vitamin D preparations after assessment of their serum levels of vitamin D.This review sought to evaluate the

benefits and harms of this Vitamin D administration to people of MS.The current level of evidence from this review is based on only

one trial with potential high risk of bias, which does not at present allow confident decision-making about the use of Vitamin D in

MS. The review authors suggest that until further high-level evidence is available, clinicians should continue to follow local guidelines

when administering vitamin D to people with MS.However, the question of the safety and effectiveness of Vitamin D in people of MS

remains unanswered.

Further research, consisting of well-designed and adequately-powered randomised controlled trials, should aim to provide reliable

evidence for people to make informed decisions as to whether this treatment can be effective in the management of MS

B A C K G R O U N D

Multiple sclerosis (MS) is an immune-mediated disease of the Cen-

tral Nervous System (CNS). Epidemiological studies have shown

a characteristic geographic distribution of MS wherein increased

incidence is seen in regions farther away from the equator (00 lat-

itude) and hence there appears to be a direct correlation of MS

occurrence and mortality with the latitude (Esparza 1995; Llorca

2005). This distribution would also appear to be supported by

circumstantial evidence implicating environmental factors of the

degree of sunlight exposure and the subsequent production of vi-

tamin D3 in skin as a predisposing factor for MS (Freedman 2000;

Ponsonby 2005).

Less than optimal blood levels of vitamin D have been linked to an

increased incidence of MS (Embry 2000; Munger 2006) and there

is also a positive association between low blood levels and relapse

in MS (Soilu-Hanninen 2005;Mowry 2010). Studies on vitamin

D supplementation in patients with MS have also shown that

the relapse rate before supplementation was significantly higher

(Goldberg 1986) and that there was a noticeable improvement in

the course of the disease after supplementation (Munger 2004).

An improved understanding of the role of vitamin D in MS has led

to the inclusion of assessment of vitamin D levels and subsequent

supplementation in the clinical management of people living with

MS.

Description of the condition

Multiple sclerosis is characterized by inflammation, demyelina-

tion and axonal damage throughout the CNS which manifests it-

self in a wide range of clinical presentations and with a variable

clinical course. Typical clinical features include visual loss, dou-

ble vision, motor weakness, spasticity, ataxia, tremor, sensory loss

or impairment, sphincter dysfunction and cognitive impairment.



The course of the disease is so variable that some people become

significantly disabled in a very short period of time, while others

can live their entire lives with only minimal or no disability.

Complex interactions between genetic susceptibility and other ex-

ternal factors such as viral infection and inadequate Vitamin D

are considered to be major determinants of MS risk (Kampman

2008).

How the intervention might work

The exogenous 1, 25-dihydroxy vitamin D3 is the hormonal form

of vitamin D3. This vitamin D hormone is generally perceived to

be important for the normal growth and development of bone,

mediated through the absorption of calcium from food and its

ultimate deposition in bone. Apart from its involvement in bone

metabolism it is also connected with the regulation of cell prolif-

eration and differentiation as well as apoptosis (Table 1) and im-

mune regulation in certain types of immune cells i.e. T helper and

dendritic cells (Niino 2008). Vitamin D intake reduces inflamma-

tory cytokines through control of gene expression (Mark 2006)

and is also involved in immunomodulatory protective effects on

the brain (Garcion 2002).

Table 1. Glossary

apoptosis A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing

harmful substances into the surrounding area

arrhythmia An abnormal heart rhythm

cytokine A small protein released by cells that has a specific effect on the interactions between cells, on communications

between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal

molecules, such as tumour necrosis factor and the interferons, which trigger inflammation and respond to

infections.

demyelination Damage of the myelin sheath of neurons

metalloprotease Proteolytic enzymes whose catalytic mechanism involves a metal, important in many aspects of biology, ranging

from cell proliferation, differentiation and remodeling of the extracellular matrix (ECM) to vascularization and

cell migration

nephrolithiasis The process of forming a kidney stone, or lower down in the urinary tract.

osteoporosis Thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein.

relapse An objective new/reemerging neurologic abnormality present for at least 24 hours in the absence of fever/infection.

It has been suggested that sub optimal levels of vitamin D may be

contributory in the process of axonal inflammation and its pro-

gression to Multiple Sclerosis, and it is also acknowledged that

relapse tends to be more common in people with low levels of

this vitamin. The precise mechanism is unclear but its role is hy-

pothesised to be as a selective immune regulator which can inhibit

this autoimmune disease.The doses required to have an immuno-

regulatory effect have been observed to be much higher than the

recommended daily intake dose (Leventis 2008)

Why it is important to do this review

Based on epidemiological data and evidence from observational

studies it has been suggested that vitamin D may help prevent MS,

reduce exacerbations and may be a useful addition to standard MS

therapy. The optimal dose of vitamin D required to have a benefi-

cial effect may be much higher than the standard supplementation

dose, and the potential hypercalcaemic side effect at such levels

can be a limitation for using this intervention (Kimball 2007). In

this review we sought to determine whether there is clear evidence

of benefit and safety for vitamin D supplementation in the man-

agement of MS.

O B J E C T I V E S



To evaluate the safety and effectiveness of vitamin D in the man-

agement of multiple sclerosis (MS)

To evaluate the hypotheses that vitamin D supplementation re-

duces disease activity, suppresses its progression, prevents devel-

opment of osteoporosis and promotes T-cell regulation in people

with MS.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all eligible randomised controlled trials and quasi-

randomised controlled trials.

Types of participants

Patients diagnosed as having clinically definite MS according

to Schumacher, Poser or McDonald’s criteria (McDonald 2001;

Polman 2005; Poser 1983; Schumacker 1965). Cases with any

pattern of the disease course (relapsing-remitting, secondary pro-

gressive and primary progressive) were included.

Exclusion criteria were allergy to any form of vitamin D, a history

of cardiac arrhythmias or any renal disease or nephrolithiasis (Table

1).

Types of interventions

All preparations of vitamin D compared to placebo or no sup-

plementation. There were no restrictions concerning route of ad-

ministration, dosage, length and frequency of treatment. Studies

comparing different doses of vitamin D were also included. Mul-

tivitamin preparations containing vitamin D were included.

Types of outcome measures

Primary outcomes

1. The mean number of relapses per patient per year or

annualised relapse rate (ARR) and proportion of patients who

remain relapse free (Table 1).

2. Time to the first treated relapse.

3. Quality of life (validated, generic or disease specific scales

i.e. MSQOL-54) (Vickrey 1995).

4. Number of patients experiencing change in the scores on

the Expanded Disability Status Scale (EDSS) (Kurtzke 1983) (at

least 1 point for EDSS < 6.0 or 0.5 point for EDSS > 5.5).

5. Safety and adverse effects: Safety and tolerability assessment

as the number of drop-outs, willingness to continue treatment

and any reported adverse events. These will be considered in the

following groups mild (not requiring intervention), moderate

(requiring treatment) and severe (life threatening or requiring

hospitalisation).

Secondary outcomes

1. Number of patients requiring hospitalisation due to

progression of the disease.

2. Cognitive functions: memory, concentration (by validated

and disease specific scales i.e. BRBNT) (Rao 1991).

3. Physical symptoms: fatigue, spasticity, spasms, bladder

function, bowel symptoms) (better, worse or no change) assessed

by questionnaire or similar instruments.

4. Psychological symptoms (better, worse or no change)

assessed by questionnaire or similar instruments.

5. Mean change in MRI parameters of disease activity

(number and/or volume of gadolinium -enhancing T1 and new

T2 lesions).

6. Serum levels of 25-hydroxyvitamin D (25(OH) vitamin D)

and calcium.

7. Bone mineral density (BMD) changes during the study

period.

8. Cytokine profile, T lymphocyte proliferation response and

Plasma metalloprotease-9 activity (Table 1).

All outcomes will have been evaluated at 6 months, 12 months

and annually thereafter. Outcomes measured at other end points

will also be considered and evaluated separately.

Search methods for identification of studies

A systematic search without language restrictions was conducted

using the optimally sensitive strategy developed for the Cochrane

Collaboration to identify all relevant published and unpublished

randomised controlled trials (Lefebvre 2009). For additional in-

formation about the Group’s search strategy please see: Cochrane

Multiple Sclerosis Group

Electronic searches

We searched the following databases:

1. The Cochrane Multiple Sclerosis Group Trials Register (17

May 2010)

2. The Cochrane Central Register of Controlled Trials

(CENTRAL) “The Cochrane Library” (Issue 2, 2010)

(Appendix 1)

3. MEDLINE (PubMed) (January 1966 to 17 May 2010)

(Appendix 2)

4. EMBASE (EMBASE.com) (1974 to 17 May 2010)

(Appendix 3)



http://www.mrw.interscience.wiley.com/cochrane/cochrane_clsysrev_crglist_fs.html




Searching other resources

In addition the following methods were used:

1. Bibliographic references of identified studies were searched

for references to additional studies.

2. Hand-searching of recent abstract books of ECTRIMS,

EFNS, ENS, AAN and ANA (1990 to 2009)

3. Personal contact with corresponding authors of relevant

trials or reviewers and other multiple sclerosis consumer societies

and experts.

4. Clinical trials registries: clinicaltrials.gov ; Current

Controlled Trials.

Data collection and analysis

Selection of studies

Two review authors (Vanitha Jagannath (VJ) and Zbys Fedorow-

icz (ZF) independently assessed the abstracts of studies resulting

from the searches. We obtained full copies of all relevant and po-

tentially relevant studies, those appearing to meet the inclusion

criteria, and those for which there were insufficient data in the title

and abstract to make a clear decision. The two authors then inde-

pendently assessed the full text papers and resolved any disagree-

ment on the eligibility of included studies through discussion and

consensus, or through a third party (GV Asokan). All irrelevant

records were excluded and details of the studies and the reasons

for their exclusion were noted in the ’Characteristics of excluded

studies’ table in RevMan 5 (Revman 2008).

Data extraction and management

The review authors collected outcome data using a pre-deter-

mined form designed for this purpose and entered the study de-

tails into the ’Characteristics of included studies’ table in RevMan

5 (Revman 2008).

The following details were extracted:

1. Trial methods: method of allocation, masking of

participants, trialists and outcomes assessors, exclusion of

participants after randomisation and proportion and reasons for

losses at follow up.

2. Participants: country of origin and location: private clinic

or academic institute, sample size, ages and the relevant inclusion

and exclusion criteria.

3. Intervention: type; dosage length of time in follow up.

4. Control: type; dosage length of time in follow up

Outcomes mentioned in the ’Types of outcome measures’ section

of the review

◦ Short term (less than 12 months) - data at 3, 6 and 12

months

◦ Medium to long term (over 1 year)

If stated, the sources of funding of any of the included studies were

recorded.

We used this information to help us to assess heterogeneity and

the external validity of the trials.

Assessment of risk of bias in included studies

Two authors independently graded the selected trial using a sim-

ple contingency form following the domain-based evaluation de-

scribed in the Cochrane Handbook for Systematic Reviews of Inter-

ventions 5.0 (Higgins 2009). The quality of this study was assessed

independently using the checklist developed for the Cochrane MS

Group. Discrepancies in judgements were to be resolved by dis-

cussion with a third reviewer however this proved unnecessary

The following domains were assessed as ’Yes’ (i.e. low risk of bias),

’Unclear’ (uncertain risk of bias) or ’No’ (i.e. high risk of bias):

1. sequence generation;

2. allocation concealment;

3. blinding (of participants, personnel and outcome assessors);

4. incomplete outcome data;

5. selective outcome reporting.

The authors reported on each of these assessments in the ’Risk of

bias in included studies’ table.

Measures of treatment effect

We did not enter any data into the RevMan analysis, but if data are

available in future updates we will calculate risk ratios (RR) and

their associated 95% confidence intervals (CIs) for dichotomous

outcomes. For continuous outcomes we will report the weighted

mean difference (WMD) or the standardized mean difference

(SMD) if different scales are used. Time-to-resolution data will be

reported as hazard ratios (HR) with their 95% CIs.

Unit of analysis issues

Only studies with a parallel group design were included so partic-

ipants will have been randomised to either intervention or control

with subsequent analysis at individual allocation level. Cross-over

studies were not included because the effects if any of vitamin D

on immune mechanisms are more likely to develop over a longer

period of time and therefore an appropriate wash-out period can-

not be clearly defined. However, in future updates, any data re-

ported from the first intervention period of such cross over trials

could be included providing it was clearly reported.

Dealing with missing data

We contacted the principal investigator of the included trial by

electronic mail and were able to obtain missing data and to clarify

some inconsistencies in the published report.



http://clinicaltrials.gov/ct2/home

http://www.controlled-trials.com/



Assessment of heterogeneity

As only one study was included in this review we did not assess

heterogeneity, but in future updates or if further data are available

the following methods of assessment will be applied.

We will assess clinical heterogeneity by examining the characteris-

tics of the studies, the similarity between the types of participants,

the interventions and the outcomes as specified in the criteria for

included studies.

Statistical heterogeneity will be assessed using a Chi2 test and the

I2 statistic where I2 values of 30% to 60% indicate moderate to

high, 50%-90% substantial and 75% to 100% considerable het-

erogeneity. We will consider heterogeneity to be significant when

the P value is less than 0.10 (Higgins 2003).

Assessment of reporting biases

The paucity of trials included in this review did not permit an as-

sessment of publication bias. In future updates we will assess pub-

lication bias by following the recommendations on testing for fun-

nel plot asymmetry as described in section 10.4.3.1 of the Cochrane

Handbook for Systematic Reviews of Interventions 5.0.2 (updated

September 2009) (Higgins 2009) and this will be explored in the

Discussion if appropriate.

Data synthesis

Two review authors (VJ and ZF) analysed the data in Review Man-

ager (Revman 2008) and reported them as specified in Chapter 9

of the Cochrane Handbook for Systematic Reviews of Interventions

5.0.2 (updated September 2009) (Higgins 2009).

There was only one included study hence we did not do the anal-

ysis. Random effects model of analysis will be applied for future

updates or if further studies are included and if there is significant

heterogeneity between the trials.

Subgroup analysis and investigation of heterogeneity

Lack of data did not permit a subgroup analysis but in future

updates and if further data become available we plan to carry out

subgroup analyses based on age, gender, category of MS, country

of residence (based on sunlight exposure), disease modifying drug

co-therapy and serum 25(OH) vitamin D levels.

Sensitivity analysis

If a sufficient number of studies had been included we would have

undertaken sensitivity analyses to assess the robustness of our re-

view results by repeating the analysis with the following adjust-

ments: exclusion of studies with unclear or inadequate allocation

concealment, blinding of outcomes assessment and completeness

of follow up.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

See: ’Characteristics of included studies’ and ’Characteristics of

excluded studies’.

Results of the search

The electronic searches retrieved 12 references to studies. After

examination of the titles and abstracts of these references all of

those which did not match our inclusion criteria and were clearly

ineligible were eliminated. We obtained full text copies of any

of the remaining potentially eligible studies and subjected them

to further evaluation. Subsequently only one study proved to be

eligible for inclusion in this review and all of the others were

excluded.

Our search of the clinical trials database (clinicaltrials.gov) re-

trieved three additional ongoing studies which will be assessed as

soon as they are published and their results become available.

Included studies

Only one study Burton 2010 was included in this review.

Characteristics of the trial setting and investigators

This open-label randomised controlled trial was conducted in the

Multiple Sclerosis Clinic at St. Michael’s Hospital, Toronto in

Canada from June 2006 to March 2008. The providers of care in

this trial were university hospital staff and the assessors of outcomes

were the investigators and other healthcare providers.

Characteristics of the participants

The sample size comprised 49 participants (40 females, 9 males)

with a mean age of 40.5 years. Of these participants 45 had relaps-

ing remitting MS and 4 had secondary progressive MS. The base-

line mean serum 25(OH)D was 78 nmol/L and the mean score

on the Expanded Disability Status Scale (EDSS) was1.34 for both

groups.

Characteristics of the interventions

The participants in the treatment group (25) were seen every six

weeks and received escalating vitamin D doses to assess tolerabil-

ity, up to 40,000 IU/day over 28 weeks to raise serum 25(OH)D

rapidly, followed by 10,000 IU/day (12 weeks) and were then

down-titrated to 0 IU/day. Supplementation with tricalcium phos-

phate (1,200mg/day) was provided throughout the study period.

Participants in the control group (24) were allowed to take the

regular dose of 4000 IU of vitamin D and “supplemental calcium

if desired”, and were seen only at the start and completion of

the study and at two intermediate time points. No assessments of

compliance as ’pill counts’ were reported for the control group.

Characteristics of the outcome measures



http://clinicaltrials.gov/ct2/home

Assessments using the Expanded Disability Status Scale (EDSS)

were carried out at baseline and at the completion of the study for

both intervention and control group.

The following biochemical tests; serum calcium, albumin, serum

25(OH)D, urine calcium/creatinine, (Ca/Cr) transaminases, urea

and creatinine and PTH levels, cytokines, lymphocyte response

and matrix metallo proteinase-9 levels (on cryopreserved samples)

were carried out at every visit for change of Vitamin D3 dose in

the intervention group at 6 weekly intervals, and in the control

group; serum 25(OH)D and calcium/albumin levels and T-cell

reactivity at weeks 1 and 52, MMP-9 and cytokines levels at weeks

1, 11, 29 and 52.

Adverse events and relapses were assessed within 72 hrs of reporting

by the clinicians and were documented. Ultrasound monitoring

for renal calculi was done at baseline, mid trial and end of the

trial, and EKG for cardiac rhythm at baseline and at the end of

the trial.

Primary endpoints were the mean change in serum calcium at

each vitamin D dose and a comparison of serum calcium between

groups. Secondary endpoints included 25(OH)D and other bio-

chemical measures, immunologic bio-markers, relapse events and

EDSS scores.

Excluded studies

All of the studies which were excluded from this review and the

reasons for their exclusion are available in the ’Characteristics of

excluded studies’ table.

Risk of bias in included studies

The single study (Burton 2010) included in this review was judged

as ’High risk of bias’ as two criteria were assessed ’no’ in the risk

of bias assessment.

Further details of this assessment are available in the relevant sec-

tion of the ’Characteristics of included studies’ table and are also

presented in the ’Risk of bias’ graph (Figure 1) and ’Risk of bias’

summary (Figure 2).

Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.

Allocation

Patients were matched for age, disease duration, baseline EDSS

score and use of disease-modifying drugs. “Members of pairs were

randomised to treatment or control groups based on blinded draw-

ing from a hat” and therefore the sequence generation was judged

as “adequate ”. The report provided insufficient information about

how the allocation sequence was concealed from the investigators

and probably not done and hence judged ’No’.

Blinding

Although the trial was blinded for outcomes of laboratory mea-

sures, neither the participants nor the trialists or outcomes asses-

sors appear to have been ’blinded’ to the interventions and there-

fore a judgement of ’no’ was given for this domain.

Incomplete outcome data

After e-mail communication with the principal investigator we

were able to clarify some of the inconsistencies in the published

report.

Two patients in each group withdrew during the trial but this was

said to be unrelated to any adverse events. A flow-chart which

tracked the participants through the trial was included in the re-

port, and the investigators analysed the data according to the in-

tention-to-treat principle, and therefore a judgement of ’yes’ was

given for this domain.

Selective reporting

The frequency of assessment of some of the clinical outcomes

varied between the intervention and control groups and could have

resulted in a degree of unintentional selective reporting in terms

of under or over disclosure of relapses or other events.

Other potential sources of bias

The use of a matched-pair study design may have restricted patient

enrolment and thereby introduced an element of selection and

volunteer bias into the trial.

Effects of interventions

Primary outcomes



The mean number of relapses per patient per year or

annualised relapse rate and proportion of patients who

remain relapse free

In the group treated with escalating doses of vitamin D compared

to control there was a reduction in annualised relapse rate as well

as a higher proportion of relapse free patients at the end of the

study period.

Time to the first treated relapse

This outcome was not reported in the included study.

Quality of life (validated and specific scales i.e. MSQOL-54)


Number of patients experiencing a change in the Expanded

Disability Status Scale (EDSS) score

In the group treated with escalating doses of vitamin D, there was

a reduction of the mean EDSS scores and a lower proportion of

patients with an increase in EDSS scores at the end of the study

Safety and adverse effects

Biochemistry profiles of renal and hepatic functions were reported

to be within normal limits and there was no evidence of renal

calcification, disturbances of cardiac rhythm or any other adverse

events.

Secondary outcomes

Number of patients requiring hospitalisation due to

progression of the disease

This outcome was not reported in the included study

Cognitive functions (memory, concentration).


Physical symptoms


Psychological symptoms


Mean change in MRI parameters of disease activity (number

and/or volume of gadolinium-enhancing T1 and new T2

lesions)


Serum levels of 25-hydroxyvitamin D (25(OH)D) and

Calcium

The serum 25(OH)D rose considerably during the dosing period

but no adverse consequences were reported.

No significant difference in serum calcium occurred at any point

along the dosing regimen, nor did any serum calcium values exceed

the upper limit of the reference range (2.10-2.60 mmol/L) in the

treatment group. The serum calcium at peak 25(OH) vitamin D

levels was within the normal range and only slightly higher in the

treatment group.

Bone mineral density (BMD) changes during the study

period


Cytokine profile, T lymphocyte proliferation response and

Plasma metalloprotease-9 activity

There were no consistent patterns of change in cytokine titers

within or between groups.

The total T-cell proliferation response decreased in the treatment

group with no change in the control group.

Plasma MMP revealed small but not statistically significant reduc-

tions between visits over the course of the trial in both treatment

and control groups.

D I S C U S S I O N

Summary of main results

Although only one trial (Burton 2010) was included in this review,

there are three ongoing studies (NCT01024777, NCT00785473,

NCT01005095) with common outcome measures which are

likely to be of relevance to this review and may ultimately provide

valuable evidence in future updates.

Overall completeness and applicability ofevidence

The single study included in this review provided some evidence

of the potential benefit of the intervention on relevant clinical out-

comes e.g. the annualised relapse rate, EDSS scores and suppres-

sion of T-cell proliferation. A measure of safety in use of high doses



of vitamin D was illustrated by the relative absence of any adverse

events or of serum calcium levels in excess of the upper limit of the

reference range over the one year study period. However, although

the case selection and matched-pair design of this exploratory trial

may have contributed towards minimising the effects of potential

confounders, it was not adequately powered to address all relevant

clinical outcomes which may ultimately impose limits on the ap-

plicability of the evidence to the MS population at large.

Quality of the evidence

Limitations in study design

Whilst recognising that the principal objective of the single in-

cluded study was to investigate the tolerability of high doses of

vitamin D this could have, to a certain extent, dictated the shape

of the study design and consequently may have an impact on the

generalisability of the evidence pertaining to the effectiveness of

the intervention. Inadequate blinding and a lack of clarity in how

the allocation sequence was concealed from investigators can con-

tribute to biased assessment of the effects of an intervention and it

is uncertain to what extent these aspects may have compromised

the quality of the evidence presented in the included study.

Inconsistency

As only one trial was included in this review this assessment was

not applicable.

Indirectness

Although the single trial met the eligibility criteria for inclusion,

inevitably the matched-pair design had an impact on patient en-

rolment and recruitment duration, both of which may have con-

tributed to an element of selection bias and thereby addressed a

restricted version of the review question in terms of the popula-

tion.

Imprecision

The limited amount of outcome data available from this single

trial did not permit any assessment of the precision of the results.

Publication bias

In view of the low number of trials included in this review this

assessment was not estimable.

Potential biases in the review process

Strident attempts were made to limit bias in the review process by

ensuring a comprehensive search for potentially eligible studies,

which included searching in clinical trial registries and in other

than the major databases but which nevertheless resulted in the

retrieval of a low number of studies.

The two authors’ independent assessments of eligibility of studies

for inclusion in this review and the extraction of data minimised

the potential for additional bias beyond that detailed in the risk

of bias tables.

Agreements and disagreements with otherstudies or reviews

We are not aware of any other reviews that have covered this re-

search question.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

The evidence from this review does not at present allow confident

decision-making about the use of Vitamin D in MS since it was

from a single low powered trial with the limitation of a potential

high risk of bias. However, some evidence for the safety and effec-

tiveness of administering high doses of vitamin D for the manage-

ment of multiple sclerosis and some benefits to patients in terms

of clinical improvement were suggested by the review.

Global variation in recommended dosage regimens for vitamin D

supplementation is attributable to regional differences in the level

of solar exposure of individuals and therefore, until further evi-

dence becomes available, clinicians should continue to base their

decisions on regional guideline recommended therapeutic regi-

mens in conjunction with their patients individual circumstances.

Assessments of serum 25(OH)D levels, which are carried out rou-

tinely as part of the clinical management of MS, can be used to

detect vitamin D insufficiency. There is no consensus presently

about the desirable and optimal levels though based on some stud-

ies a functional classification has recently been proposed to define

serum 25(OH)D levels > 40 ng/ml or > 100 nmol/l as “desir-

able”, serum levels between 20 and 40 ng/ml or 50 and 100 nmol/

l as hypovitaminosis D, levels between 10 and 20 ng/ml or 25

and 50 mmol/l as vitamin D insufficiency and 25(OH)D levels

below 10 ng/ml or 25 nmol/l as deficient (Gomez 2003; Grant

2005). Steps to increase serum 25(OH)D levels should focus on

restoring vitamin D status to adequate levels commencing with a

one-off megadose of vitamin D3 and followed by a daily intake

of 2000-4000 IU of vitamin D3. Serum 25(OH)D levels should

be checked annually, usually at the end of each winter, to ensure



optimum dosage and should include monitoring of calcium levels

and the effects of hypercalcaemia and other side effects all of which

should be reported (Diamond 2005; van der Mei 2007).

Implications for research

The present consensus on the use of vitamin D in the management

of MS is based on the hypothesis that vitamin D could potentially

reduce the inflammatory activity responsible for relapses and the

neuronal damage implicated in disability and thereby slowing the

progression of the disease. Guidelines on vitamin D supplemen-

tation for people with MS recommend not only the restoration of

serum 25(OH) D levels but also that they should reach optimal

levels which are higher than the presently considered normal levels

to obtain the suggested beneficial impact on the immunological

effects of the disease. Although this trial provided some evidence

of the safety of high dosing regimens of vitamin D, there is a need

for further randomised controlled trials which can help provide

insight into the real benefits of such dosing regimens in people

with MS.

These RCTs should be adequately powered, multi-centred and

with a focus on clinical as well as immunological and MRI out-

comes that are meaningful to people with MS. They should assess

not only the safety but also investigate more closely the benefits of

supplementation with high dosing regimens of vitamin D.

Moreover any future trials will need to be rigorous in design and

delivery, with subsequent reporting to include high quality de-

scriptions of all aspects of methodology to enable appraisal and

interpretation of results, and conform to the Consolidated Stan-

dards of Reporting Trials (CONSORT) statement.

For further research recommendations based on the EPICOT for-

mat (Brown 2006) please see (Table 2)

Table 2. Research recommendations based on a gap in the evidence of Vitamin D use in the management of Multiple sclerosis

Core elements Issues to consider Status of research for this review

Evidence

(E)

What is the current state of evidence? The systematic review identified one RCT which

matched the eligibility criteria, it provides some evi-

dence of clinical improvement by reduction in relapse

rate and EDSS scores and good evidence of safety of

high doses of vitamin D administration to people with

MS.

Population

(P)

Diagnosis, disease stage, comorbidity, risk factor, sex,

age, ethnic group, specific inclusion or exclusion crite-

ria, clinical setting

Patients diagnosed as having clinically definite MS ac-

cording to standard criteria, with any pattern of the dis-

ease course (relapsing-remitting, secondary progressive

and primary progressive)

Intervention

(I)

Type, frequency, dose, duration, prognostic

factor

Escalating doses of oral vitamin D 3 beginning with

4000 IU/day escalated over 28 weeks to 40 000 IU/day

followed by maintenance with 10 000 IU/day for 12

weeks, 4000 IU/day for 8 weeks and a 4-week wash-

out.

Comparison

(C)

Type, frequency, dose, duration, prognostic factor Control with or without a regular oral dose of 4000 I

U/day of vitamin D3

Outcome

(O)

Which clinical or patient related outcomes will the re-

searcher need to measure, improve, influence or accom-

plish?

Which methods of measurement should be used?

• ARR and relapse free patients;EDSS scores and

patients with no EDSS progression

• Safety and adverse effects

• MRI outcomes and serum calcium,25(OH) D

levels

RR for dichotomous outcomes and MD or WMD for

continuous outcomes



http://www.consort-statement.org/

Table 2. Research recommendations based on a gap in the evidence of Vitamin D use in the management of Multiple sclerosis

(Continued)

Time Stamp

(T)

Date of literature search or recommendation 17 May 2010

Study Type What is the most appropriate study design to address

the proposed question?

Randomised controlled trial (adequately powered/

multi centred)

Methods: concealment of allocation sequence

Blinding: patients, therapist, trialists, outcomes asses-

sors, data analysts

Setting: inpatient or outpatient care with follow-up 1

year or more.

EDSS = Expanded Disability Status Scale

A C K N O W L E D G E M E N T S

We acknowledge the support of the MS Review Group and the

editors who were helpful in providing valuable guidance at various

stages within the review process.

R E F E R E N C E S

References to studies included in this review

Burton 2010 {published data only}

Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R,

et al.A phase I/II dose-escalation trial of vitamin D3 and calcium in

multiple sclerosis. Neurology 2010;74(23):1852–9. [DOI:

10.1212/WNL.0b013e3181e1cec2]

References to studies excluded from this review

Ban 2000 {published data only}

Ban Y, Taniyama M, Ban Y. Vitamin D receptor gene

polymorphism is associated with Graves’ disease in the Japanese

population. Journal of Clinical Endocrinology and Metabolism 2000;

85(12):4639–43. [PUBMED: 11134121]

Ban 2000a {published data only}

Ban Y, Ban Y, Taniyama M, Katagiri T. Vitamin D receptor

initiation codon polymorphism in Japanese patients with Graves’

disease. Thyroid 2000;10(6):475–80. [PUBMED: 10907990]

Cosman 1994 {published data only}

Cosman F, Nieves J, Herbert J, Shen V, Lindsay R. High-dose

glucocorticoids in multiple sclerosis patients exert direct effects on

the kidney and skeleton. Journal of Bone and Mineral Research

1994;9(7):1097–105. [PUBMED: 7942157]

Goldberg 1986 {published data only}

Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased

relapse rate through dietary supplementation with calcium,

magnesium and vitamin D. Medical Hypotheses 1986;21(2):

193–200. [PUBMED: 3537648]

Kimball 2007 {published data only}

Kimball SM, Ursell MR, O’Connor P, Vieth R. Safety of vitamin

D3 in adults with multiple sclerosis. American Journal of Clinical

Nutrition 2007;86(3):645–51. [PUBMED: 17823429]

Lakatos 2000 {published data only}

Lakatos P, Nagy Z, Kiss L, Horvath C, Takacs I, Foldes J, et

al.Prevention of corticosteroid-induced osteoporosis by alfacalcidol.

Zeitschrift fur Rheumatologie 2000;59 Suppl 1:48–52. [PUBMED:

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Mahon 2003 {published data only}

Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT.

Cytokine profile in patients with multiple sclerosis following

vitamin D supplementation. Journal of Neuroimmunology 2003;

134(1-2):128–32. [PUBMED: 12507780]

Reichel 1992 {published data only}

Reichel H, Grussinger A, Knehans A, Kuhn K, Schmidt-Gayk H,

Ritz E. Long-term therapy with cyclosporin A does not influence

serum concentrations of vitamin D metabolites in patients with



multiple sclerosis. Clinical Investigator 1992;70(7):595–9.

[PUBMED: 1392429]

Soilu-Hanninen 2008 {published data only}

Soilu-Hanninen M, Laaksonen M, Laitinen I, Eralinna JP, Lilius

EM, Mononen I. A longitudinal study of serum 25-hydroxyvitamin

D and intact parathyroid hormone levels indicate the importance of

vitamin D and calcium homeostasis regulation in multiple sclerosis.

Journal of Neurology, Neurosurgery and Psychiatry 2008;79(2):

152–7. [PUBMED: 17578859]

Vojinovic 2005 {published data only}

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therapy on serum cytokine levels in patients with multiple sclerosis.

Srpski Arhiv Za Celokupno Lekarstvo 2005;133 Suppl 2:124–8.

[PUBMED: 16535996]

Wingerchuk 2005 {published data only}

Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers

GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for

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Neurosurgery and Psychiatry 2005;76(9):1294–6. [PUBMED:

16107372]

References to ongoing studies

NCT00785473 {published and unpublished data}

Can Vitamin D Supplementation Prevent Bone Loss in Persons

With Multiple Sclero. clinicaltrials.gov/show/NCT00119132

(accessed 30 June 2010).


The Effects of Interferon Beta Combined With Vitamin D on

Relapsing Remitting Multiple Sclerosis Patients. clinicaltrials.gov/

show/NCT01005095 (accessed 30 June 2010).


Safety and Immunologic Effect of Low Dose Versus High Dose

Vitamin D3 in Relapsing Remitting Multiple Sclerosis.

clinicaltrials.gov/show/NCT01024777 (accessed 30 June 2010).

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Burton 2010

Methods Trial registered with Clinicaltrials.gov, the National Institute of Health (ID

NCT00644904).

Open-label randomised controlled trial. St. Michael’s Hospital, Toronto, Canada

Duration: 52 weeks trial, in the period June 2006 to March 2008.

Participants 51 patients screened. 2 drop-outs before randomisation

49 allocated and randomised

INCLUSION CRITERIA:

• age18-55 years,

• clinically definite MS according to specific criteria (McDonald 2001; Polman

2005; Poser 1983; Schumacker 1965).

• EDSS score of 0-6.5.

EXCLUSION CRITERIA:

• participants with relapse within 60 days,

• steroid use within 30 days, chemotherapy within 12 months,

• pregnancy/inadequate contraception,

• vitamin D intake >4,000 IU/day, serum 25(OH)D level >50 nmol/L,

• lymphoma, granulomatous disease, cardiac arrhythmia, kidney dysfunction,

• disordered calcium metabolism.

RANDOMIZED:

n=49 (40 females, 9 males), mean age 40.5yrs (range 21-54).

Matched pairs for age, disease duration, EDSS score, and disease-modifying drug.

WITHDRAWALS/LOSSES TO FOLLOW-UP:

2 drops outs from each group

CHARACTERISTICS:

• 45 relapsing remitting MS, 4 secondary progressive MS.

• EDSS: Treatment group mean 1.46 (0-6.0); control group mean 1.23 (0-6.0).

• Disease duration: Treatment group mean 8.21yrs (range1-25), control group

mean 7.4yrs (range 1-21).

• Disease Modifying Drug used, Interferon/Glatiramer Acetate/None 12/2/11 in

treatment group 12/2/10 in control group

• Season enrolled, spring or summer/fall or winter 16/9 in treatment and 11/13 in

control groups.

BASELINE DATA

• Serum calcium: Treatment group mean 2.32 mmol/L (range 2.08 -2.57); control

group mean 2.32 mmol/L (range 2.16 -2.47)

• Serum 25(OH)D Treatment group mean 73 (range 38 to146)nmol/L; control

group mean 83 (range 38-154)nmol/L.

Interventions TREATMENT (25):

Oral Vitamin D3 at 4000 IU/day escalated over 28 weeks to 40 000 IU/day followed by

maintenance with 10 000 IU/day for 12 weeks, 4000 IU/day for 8 weeks and a 4-week

wash-out 14 000 IU/day over 52 weeks. Oral Calcium 1200mg/day was started from 2

weeks before the starting dose of vitamin D, and stopped for the last 4 weeks.

CONTROL (24):

“Control patients were permitted to take vitamin D and supplemental calcium if desired



Burton 2010 (Continued)

as before ( up to 4,000 IU/day mean of 991IU/day) ”.

Outcomes Expanded Disability Status Scale (EDSS) score and general medical exam (Week 1 &

52): intervention and control groups.

Biochemical measures (6 weekly intervals)at every change of Vitamin D3 dose visits in

the intervention group

• Serum calcium, albumin ,Serum 25(OH)D, urine calcium/creatinine, (Ca/Cr)

transaminases, urea and creatinine and PTH levels

• Cytokines, lymphocyte response and matrix metallo proteinase-9 levels (on

cryopreserved samples)

Control patients had 25(OH)D and calcium/albumin levels and T-cell reactivity testing

at weeks 1 and 52, while MMP-9 and cytokines were assessed at weeks 1, 11, 29, and 52

Adverse events and relapse were assessed within 72 hrs of reporting by the clinicians and

were documented

Ultrasound monitoring for renal calculi was done at baseline,mid trial and end of the

trial, and EKG for cardiac rhythm at baseline and end of the trial.

Notes This is the first controlled study of Vitamin D in Multiple sclerosis

The trial used the escalating dose titration schedule which minimized the risk of toxicity

at higher doses as doses were stepped up only if the previous dose was confirmed safe.

Calcium supplementation in the trial permits generalization of evidence to MS popula-

tion who are regularly calcium supplemented.

The previous trial of calcitriol in MS Wingerchuk 2005 suggested a risk of hypercal-

caemia, hence this trial sought to use vitamin D which is an inactive precursor of cal-

citriol to test for safety against the same outcome.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Quote: “Members of pairs were ran-

domised to treatment or control groups

based on blinded drawing from a hat.”

Comment: Sequence generation is ade-

quate

Allocation concealment? No Quote: “An open-la-

bel randomised prospective controlled 52-

week trial matched patients with MS for

demographic and disease characteristics,

with randomizations to treatment or con-

trol groups”

Comment: not done.

Blinding?

All outcomes

No Quote: “The trial was not powered nor

blinded to properly address clinical out-

comes”

Comment:Not done , this trial was a dose

escalation trial and blinding was probably



Burton 2010 (Continued)

not feasible

Incomplete outcome data addressed?

All outcomes

Yes Quote: “Two patients in each group with-

drew during the trial, none related to ad-

verse events”

Comment: A flow chart which tracked the

progress of participants through the trial

was provided in the report.

Free of selective reporting? Unclear Quote: “More frequent monitoring of the

treatment group could have been a factor

in the disclosure of relapses and may have

missed possible events or use of undisclosed

agents in the less frequently assessed control

group”

Comment: Selective reporting of some out-

come measures may have occurred.

Free of other bias? Unclear Quote: “The matching design limited pa-

tient enrolment and recruitment duration,

and selection and volunteer bias cannot be

ruled out”

Comment: Selection and or ’volunteering’

may have attributed to an element of allo-

cation bias.

EDSS = Expanded Disability Status Scale

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Ban 2000 Not an interventional study

Ban 2000a Not an interventional study

Cosman 1994 No intervention with vitamin D

Goldberg 1986 Non RCT, self pairing for control.

Kimball 2007 Not a RCT

Lakatos 2000 Participants included patients other than those with MS, and outcomes were not related to clinical outcomes

of MS.



(Continued)

Mahon 2003 Only non clinical outcome.

Reichel 1992 Non vitamin D intervention.

Soilu-Hanninen 2008 Not an interventional study and the control was non- MS healthy population.

Vojinovic 2005 Not a RCT, and had non-MS controls, mainly non clinical outcome measures.

Wingerchuk 2005 Not a RCT.

RCT = randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT00785473

Trial name or title Can Vitamin D Supplementation Prevent Bone Loss in Persons With Multiple Sclerosis

Methods Randomized Placebo Controlled

Participants MS patients aged between 18 to 50 years

Interventions Cholecalciferol capsules, 20,000 IU weekly and calcium carbonate 500 mg daily Vs only calcium carbonate

500 mg daily

Outcomes • Primary outcome measures: changes in BMD over the 2 year study period comparing treatment and

placebo groups

• Secondary outcome measures: cytokine expression following vitamin D supplementation

• Contribution of vitamin D from different sources (generation in the skin, diet and supplements) to

serum 25(OH) vitamin D (vitamin D status)

• Changes in parameters of lower extremity function over the 2 year study period

• The number of relapses, the time to first relapse, the number of relapse-free patients

• The number of patients without progression of disability judged by EDSS and

• Reported infections

• Ratings on a fatigue scale

Starting date November 4, 2008

Contact information Margitta T Kampman, MD, PhD, University Hospital of North Norway

Notes Several studies have shown that bone mineral density (BMD) at the femoral neck decreases with increasing

physical handicap (EDSS-score) in MS patients. Possible explanations are less weightbearing exercise or less

UV-exposure resulting in reduced vitamin D generation in the skin. Study is designed to assess whether

supplementation with vitamin D, given as a weekly dose of 20,000 IU cholecalciferol, can prevent bone loss.



NCT01005095

Trial name or title The Effects of Interferon Beta Combined With Vitamin D on Relapsing Remitting Multiple Sclerosis Patients

Methods Randomized, Interventional study

Participants Patients With Relapsing Remitting Multiple Sclerosis, age 18 to 65 years

Interventions 100,000 IU Vitamin D3 per month compared with 800IU Vitamin D3 per month

Outcomes • Primary outcome measures: Occurrence and severity of Interferon beta related flu-like symptoms and

injection site reactions.

• Secondary outcome measures: Expanded Disability Status Scale (EDSS) progression

• Relapse rate

• Quality of life.

Starting date November 2009

Contact information Ariel Miller, 972-4-8250-851

Notes To verify the hypotheses that vitamin D supplementation may ameliorate interferon beta-induced flu-like

symptoms, owing to reduced release and activity of the cytokines that are in correlation with this adverse event.

Vitamin D supplementation may also positively affect injection site reactions due to its immunomodulatory

effects. Vitamin D may also augment the therapeutic efficacy of interferon beta among multiple sclerosis

patients.

NCT01024777

Trial name or title Effect of Low Dose Versus High Dose Vitamin D3 in Relapsing Remitting Multiple Sclerosis

Methods Interventional, RCT, Double blind

Participants Patients with relapsing-remitting Multiple Sclerosis

Interventions Cholecalciferol (Vitamin D3) 10,000 IU vs 400 IU in tablet form will be taken once daily for the duration

of the trial (6 months)

Outcomes • Assess safety of high dose cholecalciferol in patients with relapsing remitting multiple sclerosis

• Assess the effects of cholecalciferol supplementation on serum immune markers in patients with

relapsing remitting multiple sclerosis

• Assess clinical effects of cholecalciferol supplementation in patients with relapsing remitting multiple

sclerosis

Starting date December 2, 2009

Contact information Christopher Eckstein, MD (410) 502-1937

Notes The purpose of this study is to determine the safety and the immunologic effects of supplementation with

low-dose and high-dose cholecalciferol (vitamin D3) in patients with relapsing-remitting multiple sclerosis.



D A T A A N D A N A L Y S E S

This review has no analyses.

A P P E N D I C E S

Appendix 1. CENTRAL search strategy

#1MeSH descriptor Multiple Sclerosis explode all trees

#2MeSH descriptor Demyelinating Diseases, this term only

#3MeSH descriptor Myelitis, Transverse, this term only

#4MeSH descriptor Optic Neuritis explode all trees

#5MeSH descriptor Encephalomyelitis, Acute Disseminated, this term only

#6“multiple sclerosis”:ti,ab,kw

#7(demyelinating NEXT disease):ti,ab,kw

#8(transverse NEXT myelitis):ti,ab,kw

#9“neuromyelitis optica”:ti,ab,kw

#10“optic neuritis”:ti,ab,kw

#11(devic):ti,ab,kw

#12“acute disseminated encephalomyelitis”:ti,ab,kw

#13(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12)

#14MeSH descriptor Cholecalciferol, this term only

#15MeSH descriptor Ergocalciferols, this term only

#16MeSH descriptor Ultraviolet Rays explode all trees

#17“vitamin D” OR cholecalciferol* OR ergocalciferol* OR “ultraviolet ray*” OR sunlight:ti,ab,kw

#18MeSH descriptor Vitamin D explode tree 1

#19“vitamin D2”:ti,ab,kw or “vitamin D3”:ti,ab,kw

#20(alfacalcidol):ti,ab,kw or (calcidiol):ti,ab,kw or (calcitriol):ti,ab,kw or (calcifediol):ti,ab,kw or (calciferol):ti,ab,kw

#21“1-alpha hydroxyvitamin D3”:ti,ab,kw or “1-alpha-hydroxy-vitamin D3”:ti,ab,kw or “1-alpha hydroxycalciferol”:ti,ab,kw or “1-

alpha-hydroxy-calciferol”:ti,ab,kw

#22“1,25 dihydroxyvitamin D3”:ti,ab,kw or “1,25-dihydroxy-vitamin D3”:ti,ab,kw or “1,25 dihydroxycholecalciferol”:ti,ab,kw or

“1,25-dihydroxycholecalciferol”:ti,ab,kw

#23“25-hydroxycholecalciferol”:ti,ab,kw or “25 hydroxyvitamin D”:ti,ab,kw or “25-hydroxy-vitaminD”:ti,ab,kw

#24(#14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23)

#25(#13 AND #24)

Appendix 2. MEDLINE (PubMed) search strategy

(((“vitamin D2” OR “vitamin D3”[Title/Abstract]) OR (“1-alpha hydroxyvitamin D3” OR “1-alpha-hydroxy-vitamin D3”[Title/

Abstract]) OR (“1-alpha hydroxycalciferol” OR “1-alpha-hydroxy-calciferol”[Title/Abstract]) OR (“1,25 dihydroxyvitamin D3” OR

“1,25-dihydroxy-vitamin D3”[Title/Abstract]) OR (“1,25 dihydroxycholecalciferol” OR “1,25-dihydroxycholecalciferol”[Title/Ab-

stract]) OR (“25 hydroxycholecalciferol” OR “25-hydroxycholecalciferol”[Title/Abstract]) OR (“25 hydroxyvitamin D” OR “25-

hydroxy-vitamin D”[Title/Abstract]) OR (alfacalcidol OR calcidiol OR calcitriol OR calciferol OR ergocalciferol OR cholecalcif-

erol[Title/Abstract])) OR (“ultra violet rays”[Title/Abstract] OR “UV rays”[Title/Abstract] OR sunlight[Title/Abstract] OR ergocalcif-

erols[Title/Abstract] OR cholecalciferol[Title/Abstract] OR “vitamin d”[Title/Abstract] OR (“Ergocalciferols”[Mesh] OR “Ultraviolet

Rays”[Mesh]) OR “Sunlight”[Mesh] OR Cholecalciferol[Mesh] OR “Vitamin D”[Mesh])) AND ((((“Multiple Sclerosis”[mh]) OR

(“Myelitis, Transverse”[mh:noexp]) OR (“Demyelinating Diseases”[mh:noexp]) OR (“Encephalomyelitis, Acute Disseminated”[mh:

noexp]) OR (“Optic Neuritis”[mh])) OR ((“multiple sclerosis”[Title/Abstract]) OR (“neuromyelitis optica”[Title/Abstract]) OR (“trans-

verse myelitis”[Title/Abstract]) OR (“encephalomyelitis”[Title/Abstract]) OR (“devic”[Title/Abstract]) OR (“optic neuritis”[Title/Ab-

stract]) OR (“demyelinating disease*”[Title/Abstract]) OR (“acute disseminated encephalomyelitis”[Title/Abstract]))) AND (((ran-



domized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR

(randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT ((animals[mh]) NOT ((animals[mh]) AND (human[mh])))))

Appendix 3. EMBASE (EMBASE.com) search strategy

’vitamin d2’:ab,ti OR ’vitamin d3’:ab,ti OR alfacalcidol:ab,ti OR calcidiol:ab,ti OR calcitriol:ab,ti OR calciferol:ab,ti OR calcifediol:

ab,ti OR ’1-alpha hydroxyvitamin d3’:ab,ti OR ’1-alpha-hydroxy-vitamin d3’:ab,ti OR ’1,25 dihydroxyvitamin d3’:ab,ti OR ’1,25-

dihydroxy-vitamin d3’:ab,ti OR ’1,25 dihydroxycholecalciferol’:ab,ti OR ’1,25-dihydroxycholecalciferol’:ab,ti OR ’25 hydroxychole-

calciferol’:ab,ti OR ’25-hydroxycholecalciferol’:ab,ti OR ’25 hydroxyvitamin d’:ab,ti OR ’25-hydroxy-vitamin d’:ab,ti OR ’vitamin d’/

exp OR ’vitamin d’:ab,ti OR ’cholecalciferol’/exp OR cholecalciferol*:ab,ti OR ergocalciferol*:ab,ti OR ’ergocalciferol’/exp OR ’ultra-

violet radiation’/exp OR ’ultraviolet rays’:ab,ti OR ’ultraviolet radiation’:ab,ti OR ’ultraviolet rays’/exp OR ’uv rays’:ab,ti OR ’sunlight’/

exp OR sunlight:ab,ti AND (’encephalomyelitis’/exp OR ’demyelinating disease’/exp OR ’multiple sclerosis’/exp OR ’myelooptic neu-

ropathy’/exp OR ’multiple sclerosis’:ab,ti OR ’neuromyelitis optica’:ab,ti OR encephalomyelitis:ab,ti OR devic:ab,ti) AND (’crossover

procedure’/exp OR ’double blind procedure’/exp OR ’controlled clinical trial’/exp OR ’clinical trial’/exp OR ’single blind procedure’/

exp OR ’randomized controlled trial’/exp OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti) OR

placebo:ab,ti OR ’double blind’:ab,ti OR ’single blind’:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti) AND [humans]/

lim AND [embase]/lim

H I S T O R Y

Protocol first published: Issue 3, 2010

Review first published: Issue 12, 2010

C O N T R I B U T I O N S O F A U T H O R S

Roles and responsibilities

Draft the protocol VJ/AG/ZF/TR/LW

Develop and run the search strategy MS Group in collaboration with the authors

Obtain copies of studies AG/ZF

Select which studies to include VJ/AG/ZF

Extract data from studies VJ/AG/ZF

Enter data into RevMan AG/ZF

Carry out the analysis AG/ZF

Interpret the analysis AG/ZF/VJ

Draft the final review VJ/AG/ZF/TR/LW



(Continued)

Update the review VJ/AG/ZF/TR/LW

D E C L A R A T I O N S O F I N T E R E S T

There are no financial conflicts of interest and the authors declare that they do not have any associations with any parties who may

have vested interests in the results of this review.

S O U R C E S O F S U P P O R T

Internal sources

• There was no source of support, Not specified.

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

The measures which evaluate the disease burden in terms of ’relapses’ are not solely the corticosteroid treated relapses because all relapses

do not require treatment with corticosteroid. Therefore we changed ’the mean number of corticosteroid-treated relapses per patient’

into ’the proportion of relapse free patients and the mean annualised relapse rate’.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Multiple Sclerosis [∗drug therapy]; Randomized Controlled Trials as Topic; Vitamin D [∗therapeutic use]; Vitamins [∗therapeutic use]

MeSH check words

Humans



Vitamin D for the management of multiple sclerosis

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